Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing

作者：Junjie Hu, Lele Zhang, Haoran Xia, Yilv Yan, Xinsheng Zhu, Fenghuan Sun, Liangdong Sun, Shuangyi Li, Dianke Li, Jin Wang, Ya Han, Jing Zhang, Dongliang Bian, Huansha Yu, Yan Chen, Pengyu Fan, Qiang Ma, Gening Jiang, Chenfei Wang, Peng Zhang · 发表于：Genome Medicine · 年份：2023 · DOI：10.1186/s13073-023-01164-9 · 被引用次数：399 · 研究领域：Immune cells in cancer、Single-cell and spatial transcriptomics、Cancer Immunotherapy and Biomarkers

BACKGROUND: Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. METHODS: We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). RESULTS: Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the he...